US20240425573A1 - Methods for treating alzheimer's disease - Google Patents

Methods for treating alzheimer's disease Download PDF

Info

Publication number
US20240425573A1
US20240425573A1 US18/707,366 US202218707366A US2024425573A1 US 20240425573 A1 US20240425573 A1 US 20240425573A1 US 202218707366 A US202218707366 A US 202218707366A US 2024425573 A1 US2024425573 A1 US 2024425573A1
Authority
US
United States
Prior art keywords
human subject
beta
antibody
tau
plasma
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
US18/707,366
Other languages
English (en)
Inventor
Laura Nisenbaum
Tianle Chen
Raj Rajagovindan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biogen MA Inc
Original Assignee
Biogen MA Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biogen MA Inc filed Critical Biogen MA Inc
Priority to US18/707,366 priority Critical patent/US20240425573A1/en
Assigned to BIOGEN MA INC. reassignment BIOGEN MA INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHEN, Tianle, NISENBAUM, Laura, RAJAGOVINDAN, Raj
Publication of US20240425573A1 publication Critical patent/US20240425573A1/en
Pending legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4709—Amyloid plaque core protein
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • This disclosure relates generally to methods for treating Alzheimer's disease.
  • AD Alzheimer's disease
  • the current disclosure describes, among other things, methods of treating Alzheimer's disease that include administering an anti-beta-amyloid antibody.
  • the present disclosure encompasses a recognition that there is a correlation between, e.g., plasma p-tau levels, amyloid beta plaque levels, and clinical progression of Alzheimer's disease in subjects being treated with an anti-beta-amyloid antibody, e.g., aducanumab. Accordingly, the present disclosure provides the insight that a p-tau level in plasma of a human subject can be used to assess and/or adjust treatment with an anti-beta-amyloid antibody.
  • the present disclosure provides the recognition that plasma p-tau levels can be useful identifying subgroups that may experience improved benefits from treatment with an anti-beta-amyloid antibody, e.g., aducanumab. Accordingly, the present disclosure provides the insight that plasma p-tau levels can be useful in identifying and/or selecting patients for treatment with an anti-beta-amyloid antibody, e.g., aducanumab.
  • plasma p-tau levels can be useful for monitoring a subject receiving a treatment with an anti-beta-amyloid antibody, e.g., aducanumab, and/or determining whether such a subject should continue to receive a treatment including an anti-beta-amyloid antibody, e.g., aducanumab.
  • an anti-beta-amyloid antibody e.g., aducanumab
  • Plasma p-tau measurements can provide benefits over present techniques, which can be invasive, painful, and time consuming. Allowing subjects (e.g., patients) and physicians access to information about how a subject is responding to treatment with an anti-beta-amyloid antibody, e.g., aducanumab, the technologies described herein can improve subject outcomes and increase subject compliance for a subject population that is already experiencing challenging signs and symptoms, and may be prone to lapses in treatment.
  • an anti-beta-amyloid antibody e.g., aducanumab
  • the present disclosure provides the insight the that plasma p-tau levels in subjects show a dose-dependent and time-dependent correlation with aducanumab treatment. These correlations provide subjects and physicians with a meaningful way to determine whether administration of aducanumab is effective for treatment of Alzheimer's Disease in a subject. For example, plasma p-tau levels in the plasma of a subject may be useful in determining an aducanumab treatment regiment that results in a subject's Alzheimer's Disease being treated, while minimizing adverse events (e.g., ARIA).
  • adverse events e.g., ARIA
  • methods do not comprise assessments and/or monitoring of other biomarkers, e.g., methods described herein may not comprise assessments and/or monitoring of CSF p-tau levels, amyloid plaques, or ⁇ 42/40 ratios.
  • the present disclosure provides evidence suggesting that a baseline level of plasma p-tau may correlate with aducanumab treatment response.
  • the present disclosure demonstrates that patients with a higher plasma p-tau level at baseline (e.g., those in the fourth quartile of baseline plasma p-tau levels) show improved response to aducanumab treatment.
  • the present disclosure encompasses a recognition that a baseline level of plasma p-tau may be useful in determining whether administration of aducanumab is effective for treatment of Alzheimer's Disease in a subject.
  • a baseline level of plasma p-tau may be used to select a patient or patient population for treatment with aducanumab.
  • methods described herein can comprise measuring a baseline level of plasma p-tau.
  • the present disclosure provides methods comprising (i) determining a p-tau level in plasma of a human subject, and (ii) administering one or more doses of an anti-beta-amyloid antibody to the human subject.
  • a p-tau level in plasma of a human subject is determined prior to the human subject receiving a dose of the anti-beta-amyloid antibody.
  • provided methods further comprise determining a p-tau level in plasma of a human subject at a first and second time point.
  • a first time point for determining a p-tau level is prior to the human subject receiving a dose of the anti-beta-amyloid antibody.
  • a second time point for determining a p-tau level is after the human subject has received at least one dose of the anti-beta-amyloid antibody.
  • a second time point for determining the level of plasma p-tau is after at least 10 doses of anti-beta-amyloid antibody have been administered to the human subject. In some embodiments, a second time point for determining the level of plasma p-tau is after at least 14 doses of anti-beta-amyloid antibody have been administered to the human subject. In some embodiments, a second time point for determining the level of plasma p-tau is after at least 19 doses of anti-beta-amyloid antibody have been administered to the human subject.
  • the human subject is administered an anti-beta-amyloid antibody periodically, e.g., every 4 weeks, over a period of 56 weeks, 78 weeks, 104 weeks, 128 weeks, 134 weeks, or longer.
  • a p-tau level in plasma of a human subject is determined at a first and second time point, where the first time point occurs before the second time point, and, if the level of plasma p-tau at a first time point is greater than the level of plasma p-tau at the second time point, the method further comprises a second or subsequent administration of the anti-beta-amyloid antibody to the human subject.
  • the second or subsequent administration of the anti-beta-amyloid antibody includes a dose of the anti-beta-amyloid antibody that is equal to or greater than the dose of the anti-beta-amyloid antibody administered to the human subject in the first administration.
  • a p-tau level in plasma of a human subject is determined at a first and second time point, where the first time point occurs before the second time point, and, if the level of plasma p-tau at a first time point is less than the level of plasma p-tau at the second time point, the method further comprises a second or subsequent administration of the anti-beta-amyloid antibody to the human subject.
  • the second or subsequent administration of the anti-beta-amyloid antibody includes a dose of the anti-beta-amyloid antibody that is equal to or less than the dose of the anti-beta-amyloid antibody administered to the human subject in the first administration.
  • a p-tau level in plasma of a human subject is determined at a first and second time point, where the first time point is a baseline or reference measurement, and the second time point occurs after administering one or more doses of anti-beta-amyloid antibody.
  • the first time point is a baseline at time point that occurs before administering anti-beta-amyloid antibody.
  • a p-tau level in plasma at a first time point is a baseline that is adjusted.
  • a p-tau level in plasma at a first time point is a baseline that is unadjusted.
  • a p-tau level in plasma at a second time point is reduced at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, or at least 15% relative to the first time point (e.g., baseline). In some embodiments, a p-tau level in plasma at a second time point is reduced at least 10% relative to the first time point (e.g., baseline).
  • a p-tau level in plasma of a human subject is compared to a reference measurement of p-tau in plasma.
  • a reference measurement of p-tau in plasma is, e.g., from healthy human subjects or human subjects diagnosed with AD that have not received treatment.
  • a p-tau level in plasma of a human subject is compared to a reference level of p-tau of subjects who have been administered placebo. In some embodiments, a p-tau level in plasma of a human subject is reduced least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 24%, or at least 25% relative to p-tau levels of a placebo group of patients at the same time point.
  • a p-tau level in plasma of a human subject has an adjusted mean change from baseline that is reduced relative to the adjusted mean change from baseline of a placebo group of patients at the same time point.
  • a p-tau level in plasma of a human subject has an adjusted mean change from baseline that is reduced at least ⁇ 0.2, ⁇ 0.25, ⁇ 0.3, ⁇ 0.35, ⁇ 0.4, ⁇ 0.45, ⁇ 0.5, ⁇ 0.55, ⁇ 0.6, ⁇ 0.65, ⁇ 0.7, ⁇ 0.75, ⁇ 0.8, ⁇ 0.85, ⁇ 0.9, ⁇ 0.95, relative to the adjusted mean change from baseline of a placebo group of patients at the same time point.
  • the time point is after a period of 56 weeks, 78 weeks, 104 weeks, 128 weeks, 134 weeks, or longer.
  • a p-tau level in plasma of a human subject has an adjusted mean change from baseline that is reduced within a range of ⁇ 0.1 to ⁇ 0.6 relative to the adjusted mean change from baseline of a placebo group of patients at the same time point.
  • a p-tau level in plasma of a human subject has an adjusted mean change from baseline that is reduced within a range of ⁇ 0.2 to ⁇ 0.7 relative to the adjusted mean change from baseline of a placebo group of patients at the same time point.
  • the present disclosure provides methods comprising (i) determining a p-tau level in plasma of a human subject at baseline, and to a subjects whose plasma p-tau level is above a reference level (ii) administering one or more doses of an anti-beta-amyloid antibody.
  • a p-tau level in plasma comprises tau with phosphorylation at one or more sites selected from: Y18, S46, T50, S69, T71, S113, T123, T153, T175, T181, S184, S85, S191, Y197, S198, S199, S202, T205, S208, S210, T212, S214, T217, T231, S235, S237, S238, S258, S262, S289, S356, Y397, S400, T403, S404, S409, S412, S413, T414/S416, S422, T427, S433, and S435.
  • a p-tau level in plasma comprises p-tau 181 and/or p-tau 217 .
  • the p-tau level is a plasma p-tau 181 level.
  • a human subject has or is suspected of having a disease associated with the accumulation and deposition of beta amyloid, such as Alzheimer's disease, Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and/or multi-infarct dementia.
  • a disease associated with the accumulation and deposition of beta amyloid such as Alzheimer's disease, Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and/or multi-infarct dementia.
  • a human subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease. In some embodiments, a subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease-intermediate likelihood by a CDR global score of 0.5 and a Memory Box score of 0.5 or greater before treatment. In some embodiments, a subject has been diagnosed with mild cognitive impairment due to Alzheimer's disease-intermediate likelihood by a history of subjective memory decline with gradual onset and slow progression over the last 1 year before treatment, e.g., as corroborated by an caregiver. In some embodiments, a subject has been diagnosed with mild Alzheimer's disease dementia by the NIA-AA core clinical criteria for probable Alzheimer's disease dementia. In some embodiments, a subject has been diagnosed with mild Alzheimer's disease dementia by a CDR score of 0.5 to 1.0 and a Memory Box score of 0.5 or greater before treatment.
  • one or more doses of an anti-beta-amyloid antibody administered to a human subject comprise one or more doses of an anti-beta-amyloid antibody selected from: aducanumab, lecanemab, gantenerumab, donanemab, LY3002813, bapineuzumab, crenezumab, MEDI-1814, and solanezumab.
  • an anti-beta-amyloid antibody comprises a VHCDR1 with the amino acid sequence of SEQ ID NO:3, a VHCDR2 with the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 with the amino acid sequence of SEQ ID NO:5, and a VLCDR1 with the amino acid sequence of SEQ ID NO:6, a VLCDR2 with the amino acid sequence of SEQ ID NO: 7, and a VLCDR3 with the amino acid sequence of SEQ ID NO:8.
  • an anti-beta-amyloid antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO:2.
  • an anti-beta-amyloid antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:10 and a light chain comprising the amino acid sequence of SEQ ID NO: 11. In some embodiments, an anti-beta-amyloid antibody is aducanumab.
  • administering an anti-beta-amyloid antibody is by intravenous administration. In some embodiments, administering an anti-beta-amyloid antibody is by subcutaneous administration.
  • provided methods comprise administering a dose of the anti-beta-amyloid antibody in an amount of 3 mg antibody/kg of body weight of the human subject. In some embodiments, provided methods comprise administering a dose of the anti-beta-amyloid antibody in an amount of 6 mg antibody/kg of body weight of the human subject. In some embodiments, provided methods comprise administering a dose of the anti-beta-amyloid antibody in an amount of 10 mg antibody/kg of body weight of the human subject.
  • provided methods comprise administering the anti-beta-amyloid antibody as a multiple dose regimen comprising multiple doses of 1 mg antibody/kg of body weight of the human patient are administered to the human patient at intervals of 4 weeks, multiple doses of 3 mg antibody/kg of body weight of the human patient are administered to the human patient at intervals of 4 weeks, multiple doses of 6 mg antibody/kg of body weight of the human patient are administered to the human patient at intervals of 4 weeks, and multiple doses of 10 mg antibody/kg of body weight of the human patient are administered to the human patient at intervals of 4 weeks.
  • provided methods comprise (a) administering a dose of the anti-beta-amyloid antibody to the human subject in an amount of 1 mg antibody/kg of body weight of the human subject; (b) 4 weeks after step (a), administering a dose of the antibody to the human subject in an amount of 1 mg antibody/kg of body weight of the human subject; (c) 4 weeks after step (b), administering a dose of the antibody to the human subject in an amount of 3 mg antibody/kg of body weight of the human subject; (d) 4 weeks after step (c), administering a dose of the antibody to the human subject in an amount of 3 mg antibody/kg of body weight of the human subject; (e) 4 weeks after step (d), administering a dose of the antibody to the human subject in an amount of 6 mg antibody/kg of body weight of the human subject; (f) 4 weeks after step (e), administering a dose of the antibody to the human subject in an amount of 6 mg antibody/kg of body weight of the human subject; and (g) in consecutive intervals of 4 weeks
  • provided methods comprise administering a dose of the antibody at a cumulative dose of at least 150 mg antibody/kg of body weight of the human subject. In some embodiments, provided methods comprise administering a dose of the antibody at a cumulative dose of at least 200 mg antibody/kg of body weight of the human subject. In some embodiments, provided methods comprise administering a dose of the antibody in an amount of 10 mg antibody/kg of body weight of the human subject every 4 weeks over at least 52 weeks. In some embodiments, provided methods comprise administering a dose of the antibody in an amount of 6 mg antibody/kg of body weight of the human subject every 4 weeks over at least 112 weeks.
  • provided methods comprise administering the antibody to the human subject in multiple doses and wherein the multiple doses comprise (a) at least two doses of 3 mg antibody/kg of body weight of the human subject every 4 weeks; and (b) at least thirty doses of 6 mg antibody/kg of body weight of the human subject every 4 weeks.
  • a human subject is an ApoE carrier. In some embodiments, a human subject has Down's syndrome. In some embodiments, a human subject is aged ⁇ 65 years. In some embodiments, a human subject is aged 65 to 74 years. In some embodiments, a human subject is aged ⁇ 75 years.
  • a human subject is aged 65 to 74 years, and said subject has a plasma p-tau level at a second time point that is reduced at least 5% to at least 20% relative to a first, baseline time point. In some embodiments, a human subject is aged 65 to 74 years, and said subject has a plasma p-tau level at a second time point that is reduced at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, or at least 15% relative to a first, baseline time point. In some embodiments, a human subject is aged 65 to 74 years, and said subject has a plasma p-tau level that is reduced at least 10% to at least 30% relative to a placebo group of patients at the same time point.
  • a human subject is aged 65 to 74 years, and said subject has a plasma p-tau level that is reduced at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, or at least 25% relative to a placebo group of patients at the same time point.
  • a p-tau level in plasma of a human subject has an adjusted mean change from baseline that is reduced at least ⁇ 0.2, ⁇ 0.25, ⁇ 0.3, ⁇ 0.35, ⁇ 0.4, ⁇ 0.45, ⁇ 0.5, ⁇ 0.55, ⁇ 0.6, ⁇ 0.65, ⁇ 0.7, ⁇ 0.75, ⁇ 0.8, ⁇ 0.85, ⁇ 0.9, ⁇ 0.95, relative to the adjusted mean change from baseline of a placebo group of patients at the same time point.
  • the time point is after a period of 56 weeks, 78 weeks, 104 weeks, 128 weeks, 134 weeks, or longer.
  • a p-tau level in plasma of a human subject has an adjusted mean change from baseline that is reduced within a range of ⁇ 0.1 to ⁇ 0.6 relative to the adjusted mean change from baseline of a placebo group of patients at the same time point.
  • a p-tau level in plasma of a human subject has an adjusted mean change from baseline that is reduced within a range of ⁇ 0.2 to ⁇ 0.7 relative to the adjusted mean change from baseline of a placebo group of patients at the same time point.
  • a human subject is aged ⁇ 75 years, and said subject has a plasma p-tau level at a second time point that is reduced at least 5% to at least 25% relative to a first, baseline time point.
  • a human subject is aged ⁇ 75 years, and said subject has a plasma p-tau level at a second time point that is reduced at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% relative to a first, baseline time point.
  • a human subject is aged ⁇ 75 years, and said subject has a plasma p-tau level that is reduced at least 20% to at least 40% relative to a placebo group of patients at the same time point.
  • a human subject is aged ⁇ 75 years, and said subject has a plasma p-tau level that is reduced at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, or at least 35% relative to a placebo group of patients at the same time point.
  • a human subject is an ApoE noncarrier, and said subject has a plasma p-tau level at a second time point that is reduced at least 5% to at least 25% relative to a first, baseline time point.
  • a human subject is an ApoE noncarrier, and said subject has a plasma p-tau level at a second time point that is reduced at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% relative to a first, baseline time point.
  • a human subject is an ApoE noncarrier, and said subject has a plasma p-tau level that is reduced at least 10% to at least 40% relative to a placebo group of patients at the same time point.
  • a human subject is an ApoE noncarrier, and said subject has a plasma p-tau level that is reduced at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, or at least 35% relative to a placebo group of patients at the same time point.
  • a human subject is an ApoE carrier, and said subject has a plasma p-tau level at a second time point that is reduced at least 5% to at least 20% relative to a first, baseline time point.
  • a human subject is an ApoE carrier, and said subject has a plasma p-tau level at a second time point that is reduced at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, or at least 15% relative to a first, baseline time point.
  • a human subject is an ApoE carrier, and said subject has a plasma p-tau level that is reduced at least 10% to at least 30% relative to a placebo group of patients at the same time point.
  • a human subject is an ApoE carrier, and said subject has a plasma p-tau level that is reduced at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, or at least 25% relative to a placebo group of patients at the same time point.
  • a human subject does not develop an Amyloid Related Imaging Abnormality (ARIA) during the course of treatment that requires suspension of treatment.
  • ARIA Amyloid Related Imaging Abnormality
  • provided methods include methods of treating Alzheimer's Disease (AD) in the human subject. In some embodiments, provided methods include methods of monitoring treatment response in the human subject. In some embodiments, provided methods include methods of determining a treatment plan for the human subject. In some embodiments, provided methods include methods of monitoring the cognitive state of the human subject.
  • AD Alzheimer's Disease
  • provided methods include methods of monitoring treatment response in the human subject.
  • provided methods include methods of determining a treatment plan for the human subject.
  • provided methods include methods of monitoring the cognitive state of the human subject.
  • provided methods include methods of characterizing or assessing efficacy of an anti-beta-amyloid antibody in a human subject.
  • the present disclosure provides methods comprising determining a p-tau level in plasma of a human subject who has received at least one dose of an anti-beta amyloid antibody, and adjusting the amount of an anti-beta-amyloid antibody in a dose administered to the human subject based on the determined plasma p-tau level.
  • the present disclosure provides methods for selecting a patient for treatment with an anti-beta-amyloid antibody comprising determining a p-tau level in plasma of a human subject.
  • the present disclosure provides methods for determining a dose of an anti-beta-amyloid antibody to be administered to a human subject comprising determining a p-tau level in plasma of a human subject.
  • the present disclosure provides methods for selecting a patient receiving an anti-beta-amyloid antibody for cognitive support services comprising determining a p-tau level in plasma of a human subject.
  • the present disclosure provides methods comprising determining a p-tau level in plasma of a human subject who has received at least one dose of an anti-beta-amyloid antibody.
  • provided methods comprise comparing the p-tau level in plasma of the human subject to a reference plasma p-tau level.
  • a reference plasma p-tau level is a p-tau level in plasma of the human subject prior to receiving a dose of an anti-beta-amyloid antibody.
  • a reference plasma p-tau level is an average p-tau level in plasma of a plurality of human subjects.
  • a plurality of human subjects are a plurality of healthy human subjects with no evidence of AD. In some embodiments, a plurality of human subjects are a plurality of human subjects with a known level of amyloid plaques. In some embodiments, a plurality of human subjects are a plurality of human subjects with a known level of tau tangles. In some embodiments, a plurality of human subjects are a plurality of human subjects with a predetermined level of cognition.
  • a human subject is classified as being susceptible to worsening cognition if the p-tau level in plasma of the human subject is higher than a reference plasma p-tau level. In some embodiments, a human subject is classified as being susceptible to increased numbers of amyloid plaques if the p-tau level in plasma of the human subject is higher than a reference plasma p-tau level. In some embodiments, a human subject is classified as being susceptible to increased numbers of tau tangles if the p-tau level in plasma of the human subject is higher than a reference plasma p-tau level.
  • provided methods comprise administering another dose of the anti-beta-amyloid antibody to the human subject if the p-tau level in plasma of the human subject is higher than a reference plasma p-tau level.
  • administering another dose of the anti-beta-amyloid antibody to the human subject comprises administering a dose of the anti-beta-amyloid antibody to the human subject that is equal to or greater than a prior dose of the anti-beta-amyloid antibody received by the human subject.
  • a p-tau level in plasma comprises tau with phosphorylation at one or more sites selected from: Y18, S46, T50, S69, T71, S113, T123, T153, T175, T181, S184, S85, S191, Y197, S198, S199, S202, T205, S208, S210, T212, S214, T217, T231, S235, S237, S238, S258, S262, S289, S356, Y397, S400, T403, S404, S409, S412, S413, T414/S416, S422, T427, S433, and S435.
  • a p-tau level in plasma comprises p-tau 181 and/or p-tau 217 .
  • the p-tau level is a plasma p-tau 181 level.
  • a human subject is an ApoE carrier. In some embodiments, a human subject has Down's syndrome. In some embodiments, a human subject is aged ⁇ 65 years. In some embodiments, a human subject is aged 65 to 74 years. In some embodiments, a human subject is aged ⁇ 75 years.
  • kits comprising a composition comprising an anti-beta-amyloid antibody for administration to a human subject and instructions for use.
  • the instructions direct administration to a human subject that has one or more characteristics.
  • the instructions direct administration to a human subject that has Down's syndrome. In some embodiments, the instructions direct administration to a human subject that is aged ⁇ 65 years. In some embodiments, the instructions direct administration to a human subject that is aged 65 to 74 years. In some embodiments, the instructions direct administration to a human subject that is aged ⁇ 75 years.
  • the instructions direct administration to a human subject that has a plasma p-tau level is above a reference or threshold level.
  • a p-tau level in plasma comprises p-tau 181 and/or p-tau 217 .
  • the p-tau level is a plasma p-tau 181 level.
  • kits for use in accordance with the present disclosure may include, instructions for processing samples, performing tests on samples, instructions for interpreting the results, etc.
  • the instructions to determine a p-tau level in plasma of a human subject at a first and second time point are prior to the human subject receiving a dose of the anti-beta-amyloid antibody.
  • a second time point for determining a p-tau level is after the human subject has received at least one dose of the anti-beta-amyloid antibody.
  • a second time point for determining the level of plasma p-tau is after at least 10 doses of anti-beta-amyloid antibody have been administered to the human subject.
  • a second time point for determining the level of plasma p-tau is after at least 14 doses of anti-beta-amyloid antibody have been administered to the human subject. In some embodiments, a second time point for determining the level of plasma p-tau is after at least 19 doses of anti-beta-amyloid antibody have been administered to the human subject.
  • the instructions direct continued administration to a human subject whose change in plasma p-tau level between the first and second time point meets or exceeds a reference or threshold level.
  • a p-tau level in plasma comprises p-tau 181 and/or p-tau 217 .
  • the p-tau level is a plasma p-tau 181 level.
  • FIG. 1 depicts a schematic of a study design for dosing an exemplary anti-Abeta (A ⁇ ) antibody, such as, e.g., aducanumab.
  • a ⁇ anti-Abeta
  • FIG. 2 shows the change from Baseline in A ⁇ PET Composite standardized uptake value ratio (SUVR) by MMRM of 18 F-florbetapir amyloid PET analysis population of Study 1. ***p ⁇ 0.0001 compared with placebo (nominal).
  • SUVR standardized uptake value ratio
  • FIG. 3 shows the change from Baseline in A ⁇ PET Composite SUVR by MMRM of 18 F-florbetapir A ⁇ PET Analysis Population of Study 2. ***p ⁇ 0.0001 compared with placebo (nominal).
  • FIG. 4 depicts the adjusted mean change in plasma p-tau 181 levels of the population of Study 1.
  • FIG. 5 depicts the adjusted mean change in plasma p-tau 181 levels of the population of Study 2.
  • FIG. 8 A and FIG. 8 B depict change from baseline plasma p-tau 181 in subjects whose baseline florbetapir amyloid PET composite SUVR was greater than >1.10 (open circles, dashed line) and in subjects whose baseline florbetapir amyloid PET composite SUVR was ⁇ 1.10 (solid circles, solid line), for the populations of patients from Study 1 and Study 2, respectively.
  • FIG. 9 depicts Forest plots of plasma p-tau 181 subgroup analysis for subjects receiving a “low dose” of an exemplary anti-A ⁇ antibody treatment.
  • FIG. 10 depicts Forest plots of plasma p-tau 181 subgroup analysis for subjects receiving a “high dose” of an exemplary anti-A ⁇ antibody treatment.
  • FIG. 11 depicts Forest plots of plasma p-tau 181 subgroup analysis based on baseline amyloid PET SUVR for subjects receiving a “high dose” of an exemplary anti-A ⁇ antibody treatment.
  • FIG. 12 depicts Forest plots of plasma p-tau 181 subgroup analysis based on baseline amyloid PET SUVR for subjects receiving a “low dose” of an exemplary anti-A ⁇ antibody treatment.
  • FIG. 13 depicts Forest plots of plasma p-tau 181 subgroup analysis based on baseline plasma p-tau 181 for subjects receiving a “high dose” of an exemplary anti-A ⁇ antibody treatment.
  • FIG. 14 depicts Forest plots of plasma p-tau 181 subgroup analysis based on baseline plasma p-tau 181 for subjects receiving a “low dose” of an exemplary anti-A ⁇ antibody treatment.
  • FIG. 15 depicts line plots of plasma p-tau 181 adjusted mean change from baseline over time for subjects in Study 1 over the placebo-controlled and long term extension periods.
  • FIG. 16 depicts line plots of plasma p-tau 181 adjusted mean change from baseline over time for subjects in Study 2 over the placebo-controlled and long term extension periods.
  • Aducanumab is a human monoclonal antbody targeting A ⁇ aggregates.
  • FDA U.S. Food and Drug Administration
  • ADUHELMTM aducanumab-avwa
  • the efficacy of ADUHELM was evaluated in two Phase 3 clinical trials—EMERGE (Study 1) and ENGAGE (Study 2)—in patients with early stages of Alzheimer's disease (mild cognitive impairment and mild dementia) with confirmed presence of amyloid pathology.
  • ADUHELM The effects of ADUHELM were also assessed in the double-blind, randomized, placebo-controlled, dose-ranging Phase 1b study, PRIME (Study 3). In these studies, ADUHELM consistently showed a dose- and time-dependent effect on the lowering of amyloid beta plaques (by 59 percent [p ⁇ 0.0001] in ENGAGE, 71 percent [p ⁇ 0.0001] in EMERGE, and 61 percent [p ⁇ 0.0001] in PRIME). Using data from the phase 3 aducanumab trials, EMERGE and ENGAGE, the present disclosure describes investigation of the effect of aducanumab treatment on plasma p-tau 181 in ⁇ 7,000 plasma samples from 1815 patients with early Alzheimer's disease.
  • administering typically refers to the administration of a composition (e.g., comprising an anti-A ⁇ antibody as described herein) to a subject to achieve delivery of an agent that is, or is included in, a composition to a target site or a site to be treated.
  • a composition e.g., comprising an anti-A ⁇ antibody as described herein
  • administration may be parenteral.
  • administration may involve a single dose or multiple doses.
  • administration may involve application of a fixed number of doses.
  • administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and/or periodic (e.g., individual doses separated by a common period of time) dosing.
  • determining can utilize or be accomplished through use of any of a variety of techniques available to those skilled in the art, including for example specific techniques explicitly referred to herein. In some embodiments, determining involves manipulation of a physical sample. In some embodiments, determining involves consideration and/or manipulation of data or information. In some embodiments, determining involves receiving relevant information and/or materials from a source. In some embodiments, determining involves comparing one or more features of a sample or entity to a comparable reference.
  • an appropriate reference measurement may be or comprise a measurement in a particular system (e.g., in a single individual) under otherwise comparable conditions absent presence of (e.g., prior to and/or after) a particular agent or treatment, or in presence of an appropriate comparable reference agent.
  • an appropriate reference measurement may be or comprise a measurement in comparable system known or expected to respond in a particular way, in presence of the relevant agent or treatment.
  • treat refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and/or reduce incidence of one or more symptoms or features of a disease, disorder, and/or condition.
  • Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition.
  • treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and/or condition, for example for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition.
  • AD Alzheimer's disease
  • ⁇ D Alzheimer's disease
  • AD is a continuum having certain operationally defined stages of disease progression.
  • AD pathology begins prior to the onset of clinical symptoms.
  • amyloid plaques one marker of AD pathology, form 10-20 years prior to the onset of AD dementia.
  • the currently recognized stages of AD include preclinical, prodromal, mild, moderate, and severe. These stages may be further divided into subcategories based on the severity of symptoms and measures of AD progression.
  • AD Alzheimer's pathological cascade. Lancet Neurol., 2010; 9 (1): 119-28).
  • NINCDS-ADRDA criteria Current core clinical criteria for all dementia, referred to as the NINCDS-ADRDA criteria (McKhann G M, V. diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Inst. on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimer's & Dementia, 7 (2011) 263-269), are known in the art and can be employed in practicing this invention. They include cognitive or behavioral impairment involving impaired ability to acquire and remember new information, impaired reasoning and handling of complex tasks, impaired visuospatial abilities, impaired language functions (speaking, reading, writing), and changes in personality, behavior, or comportment.
  • Alzheimer's disease is currently diagnosed using the core criteria and is typically characterized by symptoms which have a gradual onset over months to years, not sudden over hours or days (insidious onset). There is usually a clear-cut history of worsening of cognition by report or observation in Alzheimer's disease subjects.
  • Alzheimer's disease is mild Alzheimer's disease, early Alzheimer's disease, prodromal Alzheimer's disease, mild Alzheimer's disease dementia, mild cognitive impairment due to Alzheimer's disease, mid-stage Alzheimer's disease, or late-stage Alzheimer's disease.
  • the term “patient” includes any human subject who may benefit from therapy with an anti-beta-amyloid antibody.
  • a patient has or is suspected of having a disease associated with the accumulation and deposition of beta amyloid, such as Alzheimer's disease, Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and/or multi-infarct dementia.
  • a patient is one for whom diagnosis, prognosis, prevention, or therapy for Alzheimer's disease is desired, and includes a human subject in need of treatment.
  • Those in need of treatment include those already with AD, as well as those prone to have AD, or those in which the manifestation of AD is to be prevented.
  • Typical patients will be men or women aged 40 to 90 (e.g., 45 to 90, 50 to 90, 55 to 90, 60 to 90).
  • a patient is aged ⁇ 65 years. In some embodiments, a patient is aged 65 to 74 years. In some embodiments, a patient is aged ⁇ 75 years.
  • the disclosure provides a method of treating a patient with AD (including, without limitation, patients with preclinical, prodromal, mild, moderate, or severe AD). In certain instances, the disclosure provides a method of treating a patient with prodromal Alzheimer's disease. In some instances, the disclosure provides a method of treating a patient with early Alzheimer's disease. In some instances, the disclosure provides a method of treating a patient to reduce clinical decline in Alzheimer's disease. In some embodiments, a patient with Alzheimer's disease also has Down's syndrome.
  • the disclosure provides a method of treating a patient with mild cognitive impairment due to Alzheimer's disease. In other instances, the disclosure provides a method of treating a patient with mild Alzheimer's disease dementia.
  • the patient has amyloid pathology confirmed, e.g., by positron emission tomography (PET) imaging.
  • PET positron emission tomography
  • amyloid ⁇ pathology is confirmed by [ 18 F]-florbetapir PET imaging.
  • amyloid ⁇ pathology is confirmed by [ 18 F]-flutemetomol PET imaging.
  • amyloid ⁇ pathology is confirmed by [ 18 F]-florbetaben PET imaging.
  • amyloid ⁇ pathology is confirmed by CSF amyloid ⁇ analysis.
  • amyloid ⁇ pathology is confirmed by blood amyloid ⁇ analysis. In some cases, amyloid ⁇ pathology is confirmed by Congo red staining and birefringence under polarized microscopy. In some cases, amyloid ⁇ pathology is confirmed by immunohistochemistry (IHC), electron microscopy, or mass spectrometry. In some cases, amyloid ⁇ pathology is confirmed by any method to assess levels of amyloid ⁇ .
  • the disclosure provides a method of treating a patient with Down's syndrome that also has or is suspected of having an accumulation of beta amyloid deposits.
  • a patient with Down's syndrome has a confirmed amyloid pathology.
  • a patient with Down's syndrome has been diagnosed with AD.
  • a patient to be treated has an mini-mental state examination (MMSE) score between 24-30 (inclusive).
  • MMSE mini-mental state examination
  • the patient to be treated has a CDR global score of 0.5.
  • the patient to be treated has a RBANS score of less than or equal to 85 (based upon Delayed Memory Index score).
  • the patient to be treated has at least 6 years of work experience.
  • the patient to be treated has an MMSE score between 24-30 (inclusive); a CDR global score of 0.5; and a RBANS score of less than or equal to 85 (based upon Delayed Memory Index score).
  • the patient is an ApoE carrier (e.g., ApoE4 positive).
  • the patient is an ApoE noncarrier (e.g., ApoE4 negative).
  • the patient to be treated has mid-stage Alzheimer's disease, characterized by a MMSE score of about 10-20 or equivalent score on other scales.
  • late-stage Alzheimer's disease is characterized by an MMSE score of about 9 or less or equivalent score on other scales.
  • a patient has p-tau tangles, p-tau threads, and/or p-tau neuritic plaques. In some embodiments, a patient has neocortical p-tau tangles, neocortical p-tau threads, and/or neocortical p-tau neuritic plaques. In some embodiments, p-tau tangles, p-tau threads, and/or p-tau neuritic plaques are detected in a patient by positron emission tomography (PET) scanning of the human subject's brain.
  • PET positron emission tomography
  • p-tau tangles, p-tau threads, and/or p-tau neuritic plaques are detected in a patient by analysis of the amount of p-tau and/or t-tau in the human subject's CSF and/or plasma.
  • AD patients in need of treatment range from subjects with amyloid pathology and early neuronal degeneration to subjects with widespread neurodegeneration and irreversible neuronal loss with progressive cognitive and functional impairment to subjects with dementia.
  • Patients with preclinical AD can be identified by asymptomatic stages with or without memory complaints and emerging episodic memory and executive function deficits. This stage is typically characterized by the appearance of in vivo molecular biomarkers of AD and the absence clinical symptoms.
  • Prodromal AD patients are pre-dementia stage characterized predominantly by cognitive deficits and emerging functional impairment with disease progression.
  • Prodromal AD patients typically have mini-mental state examination (MMSE) scores between 24-30 (inclusive), a spontaneous memory complaint, objective memory loss defined as a free recall score of ⁇ 27 on the Free and Cued Selective Reminding Test (FCSRT), a global Clinical Dementia Rating (CDR) score of 0.5, absence of significant levels of impairment in other cognitive domains, and essentially preserved activities of daily living, and an absence of dementia.
  • MMSE mini-mental state examination
  • FCSRT Free and Cued Selective Reminding Test
  • CDR Clinical Dementia Rating
  • Basing AD diagnosis on clinical symptoms mild stage AD patients will exhibit conspicuous behavior at work, forgetfulness, mood swings, and attention disturbances.
  • Moderate stage AD patients will exhibit cognitive deficits, restricted everyday activities, orientation disturbance, apraxia, agnosia, aphasia, and behavioral abnormalities.
  • Severe stage AD patients are characterized by loss of independence, decay of memory and speech, and incontinence.
  • treatment is of earlier-stage patients who are amyloid positive as assessed by [ 18 F]-florbetapir PET scans. In certain embodiments, treatment is of earlier-stage patients who are amyloid positive as assessed by 18 F-flutemetomol PET scans. In certain embodiments, treatment is of earlier-stage patients who are amyloid positive as assessed by 18F-florbetaben PET scans.
  • the human subject is confirmed to have a brain amyloid beta pathology prior to the initiation of treatment.
  • the patient may be asymptomatic for, or exhibit only transient symptoms of, headache, confusion, gait difficulties, or visual disturbances.
  • the patient may or may not be an ApoE carrier (e.g., ApoE4 carrier) as determined by ApoE genotyping.
  • treatment is of patients having any medical or neurological condition (other than AD) that might be a contributing cause of the subject's cognitive impairment, such as stroke or other cerebrovascular condition, other neurodegenerative disease, a history of clinically significant psychiatric illness, acute or sub-acute micro- or macro hemorrhage, prior macrohemorrhage, or superficial siderosis.
  • a medical or neurological condition other than AD
  • these patients can be treated following screening and selection by a qualified clinician.
  • anti-beta amyloid antibodies known in the art, including, for example, aducanumab, lecanemab, gantenerumab, donanemab, LY3002813, bapineuzumab, crenezumab, MEDI-1814, and solanezumab.
  • an anti-beta amyloid antibody used in a method of the present disclosure is or comprises lecanemab. In some embodiments, an anti-beta amyloid antibody used in a method of the present disclosure is or comprises gantenerumab. In some embodiments, an anti-beta amyloid antibody used in a method of the present disclosure is or comprises donanemab. In some embodiments, an anti-beta amyloid antibody used in a method of the present disclosure is or comprises LY3002813. In some embodiments, an anti-beta amyloid antibody used in a method of the present disclosure is or comprises bapineuzumab.
  • an anti-beta amyloid antibody used in a method of the present disclosure is or comprises crenezumab. In some embodiments, an anti-beta amyloid antibody used in a method of the present disclosure is or comprises MEDI-1814. In some embodiments, an anti-beta amyloid antibody used in a method of the present disclosure is or comprises solanezumab.
  • an anti-beta amyloid antibody used in a method of the present disclosure comprises aducanumab (also known as BIIB037).
  • Aducanumab is an anti-A ⁇ antibody that recognizes aggregated forms of A ⁇ , including plaques.
  • BIIB037 contains a human kappa light chain.
  • BIIB037 consists of 2 heavy and 2 human kappa light chains connected by inter-chain disulfide bonds.
  • “BIIB037” or “aducanumab” is meant an anti-A ⁇ antibody comprising the amino acid sequences set forth in SEQ ID NOs: 10 and 11.
  • VH and VL of antibody BIIB037 have amino acid sequences that are identical to the amino acid sequence of the VH and VL of antibody NI-101.12F6A described in U.S. Pat. No. 8,906,367 (see, Tables 2-4; incorporated by reference in its entirety herein).
  • antibody BIIB037 has an antigen binding domain comprising VH and VL variable regions depicted in Table A (VH) and Table B (VL), corresponding complementarity determining regions (CDRs) depicted in Table C, and heavy and light chains depicted in Table D (H) and Table E (L).
  • VH CDRs VH CDRs (Kabat definition) underlined.
  • Variable heavy chain sequence QVQLVESGGG VVQPGRSLRL SCAASGFAFS SYGMH WVRQA PGKGLEWVA V IWFDGTKKYY TDSVKG RFTI SRDNSKNTLY LQMNTLRAED TAVYYCAR DR GIGARRGPYY MDV WGKGTTV TVSS (SEQ ID NO: 1)
  • V L CDRs V L CDRs (Kabat definition) underlined.
  • Variable light chain sequence (kappa or lambda) DIQMTQSPSS LSASVGDRVT ITC RASQSIS SYLN WYQQKP GKAPKLLIY A ASSLQS GVPS RFSGSGTD FTLTISSLQP EDFATYYC QQ SYSTPLT FGG GTKVEIKR (SEQ ID NO: 2)
  • amino acid sequence of the mature heavy chain of BIIB037 is provided in Table D below.
  • Heavy chain sequence QVQLVESGGG VVQPGRSLRL SCAASGFAFS SYGMH WVRQA PGKGLEWVA V IWFDGTKKYY TDSVKG RFTI SRDNSKNTLY LQMNTLRAED TAVYYCAR DR GIGARRGPYY MDV WGKGTTV TVSSASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP VTVSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN HKPSNTKVDK RVEPKSCDKT HTCPPCPAPE LLGGPSVFLF PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV KFNWYVDGVE VHNAKTKPRE EQYNSTYRVV SVLTVLHQDW LNGKEYKCK
  • amino acid sequence of the mature light chain of BIIB037 is provided in Table E below.
  • this disclosure contemplates the use of the other anti-Abeta-amyloid antibodies, such as antibodies comprising either the VH region comprising or consisting of SEQ ID NO:1 or the VL region comprising or consisting of SEQ ID NO:2, or antibodies comprising the VH region comprising or consisting of SEQ ID NO: 1 and the VL region comprising or consisting of SEQ ID NO:2, wherein the VH and/or VL regions have one or more substitutions, deletions, and/or insertions.
  • antibodies comprising either the VH region comprising or consisting of SEQ ID NO:1 or the VL region comprising or consisting of SEQ ID NO:2, or antibodies comprising the VH region comprising or consisting of SEQ ID NO: 1 and the VL region comprising or consisting of SEQ ID NO:2, wherein the VH and/or VL regions have one or more substitutions, deletions, and/or insertions.
  • these VH and VL regions may have up to 25, up to 20, up to 15, up to 10, up to 5, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid substitutions and still bind beta-amyloid. In specific embodiments, these amino acid substitutions occur only in the framework region. In some embodiments, the amino acid substitution(s) is/are conservative amino acid substitutions. In certain embodiments, the VH and VL regions may include 1 to 5 (1, 2, 3, 4, 5) amino acid deletions and/or additions and still bind beta-amyloid. In certain embodiments, these deletions and/or additions are made at the N- and/or C-terminus of the VH and/or VL regions. In some embodiments, one amino acid is deleted and/or added at the N and/or C-terminus of the VH region. In some embodiments, one amino acid is deleted and/or added at the N and/or C-terminus of the VL region.
  • antibodies contemplated for use in the disclosure include antibodies comprising the variable heavy chain (VH) CDRs and the variable light chain (VL) CDRs in Table C.
  • the anti-beta amyloid antibodies comprise the CDRs comprising or consisting of the amino acid sequences of SEQ ID NOs.: 3-8.
  • the anti-beta amyloid antibodies comprise the CDRs comprising or consisting of the amino acid sequences of SEQ ID NOs.: 4-8 and include as VH CDR1 an amino acid sequence comprising or consisting of GFAFSSYGMH (SEQ ID NO:9).
  • the disclosure encompasses anti-Abeta-amyloid antibodies comprising the VH and VL CDRs of BIIB037 based on any CDR definition (e.g., Kabat, Chothia, enhanced Chothia, AbM, or contact definition). See, e.g., http://www.bioinf.org.uk/abs/index.html.
  • the disclosure encompasses anti-Abeta-amyloid antibodies comprising the VH and VL CDRs of BIIB037 based on the Chothia definition.
  • the disclosure encompasses anti-Abeta-amyloid antibodies comprising the VH and VL CDRs of BIIB037 based on the enhanced Chothia definition. In some embodiments, the disclosure encompasses anti-Abeta-amyloid antibodies comprising the VH and VL CDRs of BIIB037 based on the AbM definition. In yet another embodiment, the disclosure encompasses anti-Abeta-amyloid antibodies comprising the VH and VL CDRs of BIIB037 based on the contact definition.
  • Antibody BIIB037 and other antibodies employed in the invention can be prepared using known methods.
  • the antibody is expressed in a Chinese hamster ovary (CHO) cell line.
  • the maximum tolerated amount of the anti-A ⁇ antibody is that quantity of the antibody which will produce a clinically significant response in the treatment of Alzheimer's disease consistent with safety.
  • a principal safety concern in treating patients according to the method of the invention is the occurrence of ARIA, especially ARIA-E or ARIA-H.
  • the methods of the invention make it possible to employ higher doses of antibody BIIB037 for the treatment of patients for AD than was feasible using previously known protocols.
  • dose adjustments can be implemented during the treatment protocol. For example, for reasons of safety or efficacy, doses can be increased so that the effects of the anti-A ⁇ antibody on AD can be enhanced or doses can be decreased so that the ARIA rate and severity can be mitigated. If a dose is missed, the patient should preferably resume dosing by receiving the missed dose and continuing thereafter according to the described regimen.
  • the anti-A ⁇ antibody is administered to the patient by intravenous infusion following dilution into saline.
  • each infusion step in the titration regime of the invention will typically take about 1 hour.
  • the dose ranges and other numerical values herein include a quantity that has the same effect as the numerically stated amount as indicated by treatment of Alzheimer's disease in the patient and a reduction in the incidence or susceptibility of the patient to ARIA when compared to an individual not treated by the method of the invention.
  • each numerical parameter should be construed in light of the number of significant digits, applying ordinary rounding techniques.
  • any numerical value inherently contains certain errors from the standard deviation of its measurement and such values are within the scope of the invention.
  • a method of treatment of AD described herein includes: (a) inhibiting AD, e.g. arresting its development; (b) relieving AD, e.g. causing regression of AD; or (c) prolonging survival as compared to expected survival if not receiving treatment.
  • the treatment is therapeutic. In some embodiments, treatment has a disease modifying effect.
  • a disease modifying effect means that the treatment slows or delays the underling pathological or pathophysiological disease processes and/or there is an improvement in clinical signs and symptoms of AD relative to placebo.
  • treatment results in symptomatic improvement. This may consist of enhanced cognition, more autonomy, and/or improvement in neuropsychiatric and behavioral dysfunction, even if for only a limited duration.
  • the disclosure relates to methods for delaying clinical decline or progression of disease, or relief of symptoms.
  • Delaying clinical decline or disease progression directly impacts the patient and care-givers. It delays disability, maintains independence, and allows the patient to live a normal life for a longer period of time. Relief of symptoms to the best degree possible can incrementally improve cognition, function, and behavioral symptoms, as well as mood.
  • the present disclosure describes, among other things, a titration regimen (sequential administration of increasing doses of an anti-beta amyloid antibody) to treat Alzheimer's disease.
  • the Alzheimer's disease is mild Alzheimer's disease, early Alzheimer's disease, prodromal Alzheimer's disease, mild Alzheimer's disease dementia, or mild cognitive impairment due to Alzheimer's disease.
  • the anti-beta amyloid antibody is administered to a human patient in increasing amounts over a period of time.
  • This procedure of sequentially administering the antibody to the patient is referred to herein as “titration” because it involves administering a standardized pharmaceutical of known concentrations in carefully measured amounts until completion of the procedure.
  • the titration regimen of the invention makes it possible to administer higher doses of the monoclonal antibody to AD patients without incurring the same extent of ARIA observed with a standard dose regimen.
  • the higher dose comprises a dose or doses of the anti-A ⁇ antibody of 10 mg/kg of the body weight of the subject. Without intending to be limited to any particular mechanism, it is believed that titration results in lower initial amyloid removal and slower removal during the overall treatment.
  • Titration of the anti-A ⁇ antibody is carried out in multiple doses. For example, two doses of the antibody can be administered to the patient in an amount per dose that is less than the minimum therapeutic amount, followed by 4 doses of the antibody in an amount per dose that is about equal to the minimum therapeutic amount. This regime can then be followed by multiple doses in an amount per dose that is more than the minimum therapeutic amount, but less than the maximum tolerated amount until there is an acceptable change in AD in the patient. For example, doses can be administered approximately 4 weeks apart over approximately 52 weeks (a total of 14 doses). Progress can be monitored by periodic assessment.
  • the disclosure features a method for reducing tau or treating Alzheimer's disease by reducing Abeta and/or tau in a human patient in need thereof, the method comprising sequentially administering multiple doses of an anti-A ⁇ antibody (e.g., BIIB037) in increasing amounts over a period of time to the human patient, wherein multiple doses of 1 mg antibody/kg of body weight of the human patient are administered to the human patient at intervals of about 4 weeks; multiple doses of 3 mg antibody/kg of body weight of the human patient are administered to the human patient at intervals of about 4 weeks; multiple doses of 6 mg antibody/kg of body weight of the human patient are administered to the human patient at intervals of about 4 weeks; and multiple doses of 10 mg antibody/kg of body weight of the human patient are administered to the human patient at intervals of about 4 weeks.
  • Multiple doses means at least two (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 123, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30) doses.
  • Protocol A An exemplary protocol according to the disclosure, designated Protocol A, comprises:
  • Protocol A comprises administering a first dose of anti-beta amyloid antibody to the patient in an amount of 1 mg/kg of body weight of the patient, followed by a second dose in an amount of 1 mg/kg of body weight four weeks after the first dose.
  • antibody doses 3 and 4 are administered to the patient in an amount of 3 mg/kg of body weight.
  • doses 5 and 6 of the antibody are administered to the patient in an amount of 6 mg/kg of body weight.
  • antibody dose 7 is administered to the patient in an amount of 10 mg/kg of body weight.
  • administering In some instances, after dose 7 of Protocol A, 5, 6, 7, 8, 9, or 10 doses of the anti-beta amyloid antibody in an amount of 10 mg/kg of body weight are administered to the patient. In certain instances, at least 10, at least 11, at least 12, at least 13, or at least 14 doses of the anti-beta amyloid antibody in an amount of 10 mg/kg of body weight of the subject are administered to the patient. In certain instances, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 doses of the anti-beta amyloid antibody in an amount of 10 mg/kg of body weight of the subject are administered to the patient.
  • 15 to 16, 15 to 17, 15 to 18, 15 to 19, 15 to 20, 15 to 21, 15 to 22, 15 to 23, 15 to 24, or 15 to 25 doses of the anti-beta amyloid antibody in an amount of 10 mg/kg of body weight of the subject are administered to the patient.
  • the doses mentioned above are administered in consecutive intervals of 4 weeks.
  • the doses mentioned above are administered to the patient intravenously.
  • At least 10 doses of the anti-beta amyloid antibody in an amount of 10 mg/kg of body weight of the subject are administered (e.g., intravenously) to the patient in uninterrupted 4 week intervals.
  • Protocol B Another exemplary protocol according to the disclosure, designated Protocol B, comprises:
  • step (d) of Protocol B additional doses of the anti-beta amyloid antibody in an amount of 10 mg/kg of body weight are administered to the patient.
  • at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 doses of the anti-beta amyloid antibody in an amount of 10 mg/kg of body weight of the subject are administered to the patient.
  • at least 21, at least 22, at least 23, at least 24, at least 24, or at least 25 doses of the anti-beta amyloid antibody in an amount of 10 mg/kg of body weight of the subject are administered to the patient.
  • 11 to 12, 11 to 13, 11 to 14, 11 to 15, 11 to 16, 11 to 17, 11 to 18, 11 to 19, 11 to 20, or 11 to 25 doses of the anti-beta amyloid antibody in an amount of 10 mg/kg of body weight of the subject are administered to the patient.
  • the additional doses mentioned above are administered in consecutive intervals of 4 weeks.
  • the doses mentioned above are administered to the patient intravenously.
  • ARIA Amyloid Related Imaging Abnormality
  • ARIA-E Amyloid Related Imaging Abnormality
  • the patient when the patient develops an Amyloid Related Imaging Abnormality (ARIA) during the course of treatment under Protocol A or B, the patient continues to be administered the doses described above without reduction of the dosage. In some instances, the dosage may be administered after the ARIA resolves.
  • ARIA Amyloid Related Imaging Abnormality
  • the patient upon resumption of the treatment should continue at the same or higher dose. For example if the patient has already received two 3 mg/kg doses of the anti-beta amyloid antibody before interruption, upon resumption of treatment, the patient should be administered the 6 mg/kg dose. If the patient has already received two 6 mg/kg doses of the anti-beta amyloid antibody before interruption, upon resumption of treatment, the patient should be administered the 10 mg/kg dose.
  • the patient should be administered a 10 mg/kg dose and continue to be administered the 10 mg/kg dose for as long as possible.
  • the disclosure also features methods and compositions for treating mild Alzheimer's disease, early Alzheimer's disease, prodromal Alzheimer's disease, mild Alzheimer's disease dementia, or mild cognitive impairment due to Alzheimer's disease in a human subject in need thereof.
  • the method involves administering to the human subject multiple doses of an anti-Abeta-amyloid antibody, wherein the method comprises administering in consecutive intervals of 4 weeks at least 6 doses of the antibody, wherein each dose is in an amount of 10 mg/kg of body weight of the subject. In some instances, the method comprises administering in consecutive intervals of 4 weeks at least 7 doses of the antibody, wherein each dose is in an amount of 10 mg/kg of body weight of the subject.
  • the method comprises administering in consecutive intervals of 4 weeks at least 8 doses of the antibody, wherein each dose is in an amount of 10 mg/kg of body weight of the subject. In some instances, the method comprises administering in consecutive intervals of 4 weeks at least 9 doses of the antibody, wherein each dose is in an amount of 10 mg/kg of body weight of the subject. In some instances, the method comprises administering in consecutive intervals of 4 weeks at least 10 doses of the antibody, wherein each dose is in an amount of 10 mg/kg of body weight of the subject. In some instances, the method comprises administering in consecutive intervals of 4 weeks at least 11 doses of the antibody, wherein each dose is in an amount of 10 mg/kg of body weight of the subject.
  • the method comprises administering in consecutive intervals of 4 weeks at least 12 doses of the antibody, wherein each dose is in an amount of 10 mg/kg of body weight of the subject. In some instances, the method comprises administering in consecutive intervals of 4 weeks at least 13 doses of the antibody, wherein each dose is in an amount of 10 mg/kg of body weight of the subject. In some instances, the method comprises administering in consecutive intervals of 4 weeks at least 14 doses of the antibody, wherein each dose is in an amount of 10 mg/kg of body weight of the subject. In some instances, the method comprises administering in consecutive intervals of 4 weeks at least 15 doses of the antibody, wherein each dose is in an amount of 10 mg/kg of body weight of the subject.
  • all of the doses specified are administered without interruption even if the human subject develops an ARIA during the course of treatment. In certain instances, even if the doses are interrupted due to ARIA or other side effects, the treatment is continued at the same or higher dose of the antibody. If the patient was at the highest dose of Protocol A (10 mg/kg), upon resuming treatment after an interruption, the patient is to continue to be administered a 10 mg/kg dose of the antibody.
  • the anti-beta amyloid antibody of the protocols and methods above comprises a VH and VL comprising the six CDRs of BIIB037. In certain instances, the anti-beta amyloid antibody comprises the VH and VL of BIIB037. In other instances, the anti-beta amyloid antibody comprises the heavy and light chains of BIIB037.
  • the anti-Abeta-amyloid antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises a complementarity determining region (VHCDR1) with the amino acid sequence of SEQ ID NO:3, a VHCDR2 with the amino acid sequence of SEQ ID NO: 4, and a VHCDR3 with the amino acid sequence of SEQ ID NO:5, and wherein the VL comprises a VLCDR1 with the amino acid sequence of SEQ ID NO:6, a VLCDR2 with the amino acid sequence of SEQ ID NO:7, and a VLCDR3 with the amino acid sequence of SEQ ID NO: 8.
  • VH heavy chain variable region
  • VL light chain variable region
  • the anti-beta amyloid antibody comprises a VH comprising or consisting of SEQ ID NO: 1; and a VL comprising or consisting of SEQ ID NO:2.
  • the anti-Abeta-amyloid antibody comprises a heavy chain and a light chain, wherein: the heavy chain comprises or consists of SEQ ID NO:10; and the light chain comprises or consists of SEQ ID NO: 11.
  • Plasma levels of phosphorylated tau (p-tau) are increased in A ⁇ positive human patients with mild cognitive impairment and further increased in A ⁇ positive human patients with AD.
  • Clinical progression of AD is associated with changes in a number of different biomarkers prior to detection of measures of atrophy by MRI or changes in global cognition and ADL function.
  • a ⁇ 42 (CSF and plasma) levels are among the first detectable changes, associated with cortical A ⁇ pathology, followed by changes in amyloid detected by PET, and then by changes in p-tau in CSF and plasma. See Hansson O. Nat Med. 2021; 27:954-963, incorporated herein by reference in its entirety.
  • soluble p-tau may mediate the relationship between amyloid aggregates and tau aggregates.
  • increased levels of amyloid aggregates may lead to increased levels of soluble p-tau, which may in turn lead to increased tau tangle density.
  • the present disclosure encompasses a recognition that a reduction in amyloid aggregates may result in reduced p-tau levels, which could slow of accumulation of tau aggregates (and consequent clinical decline).
  • Various methods of the present disclosure include a step of determining a p-tau level in plasma of a human subject.
  • Tau can be phosphorylated at a variety of different positions.
  • p-tau is phosphorylated at one or more positions selected from: Y18, S46, T50, S69, T71, S113, T123, T153, T175, T181, S184, S85, S191, Y197, S198, S199, S202, T205, S208, S210, T212, S214, T217, T231, S235, S237, S238, S258, S262, S289, S356, Y397, S400, T403, S404, S409, S412, S413, T414/S416, S422, T427, S433, and S435.
  • a p-tau is or includes a phosphorylation at position 181, also referred to herein as p-tau 181 .
  • a p-tau is or includes a phosphorylation at position 217, also referred to herein as p-tau 217 .
  • a p-tau level in plasma of a human subject is determined at one or more time points.
  • a p-tau level in plasma of a human subject is determined at a first and second time point, where the first time point is a baseline or reference measurement, and the second time point occurs after administering one or more doses of anti-beta-amyloid antibody.
  • the first time point is a baseline at time point that occurs before administering anti-beta-amyloid antibody.
  • a p-tau level in plasma at a first time point is a baseline that is adjusted.
  • a p-tau level in plasma at a first time point is a baseline that is unadjusted.
  • a p-tau level in plasma at a second time point is reduced at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, or at least 15% relative to a first time point (e.g., baseline). In some embodiments, a p-tau level in plasma at a second time point is reduced at least 10% relative to the first time point (e.g., baseline).
  • a p-tau level in plasma of a human subject is compared to a reference measurement of p-tau in plasma.
  • a reference measurement of p-tau in plasma is, e.g., from healthy human subjects or human subjects diagnosed with AD that have not received treatment.
  • a p-tau level in plasma of a human subject is compared to a reference level of p-tau of subjects who have been administered placebo. In some embodiments, a p-tau level in plasma of a human subject is reduced least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 24%, or at least 25% relative to p-tau levels of a placebo group of patients at the same time point.
  • the present disclosure provides methods of treating, monitoring, and/or evaluating a disease associated with the accumulation and deposition of beta amyloid, such as Alzheimer's disease, Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and/or multi-infarct dementia.
  • a disease associated with the accumulation and deposition of beta amyloid such as Alzheimer's disease, Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and/or multi-infarct dementia.
  • provided methods include methods of treating a human subject. In some embodiments, provided methods include methods of monitoring treatment response in a human subject. In some embodiments, provided methods include methods of determining a treatment plan for a human subject. In some embodiments, provided methods include methods of monitoring the cognitive state of a human subject.
  • the present disclosure provides methods for selecting a patient for treatment with an anti-beta-amyloid antibody comprising determining a p-tau level in plasma of a human subject. In some embodiments, the present disclosure provides methods for determining a dose of an anti-beta-amyloid antibody to be administered to a human subject comprising determining a p-tau level in plasma of a human subject. In some embodiments, the present disclosure provides methods for selecting a patient receiving an anti-beta-amyloid antibody for cognitive support services comprising determining a p-tau level in plasma of a human subject.
  • provided methods include methods of characterizing or assessing efficacy of an anti-beta-amyloid antibody in a human subject comprising determining a p-tau level in plasma of the human subject.
  • the present disclosure provides methods of monitoring treatment response in a human subject having or suspected of having a disease associated with the accumulation and deposition of beta amyloid, such as Alzheimer's disease, Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and/or multi-infarct dementia comprising determining a p-tau level in plasma of a human subject.
  • a disease associated with the accumulation and deposition of beta amyloid such as Alzheimer's disease, Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and/or multi-infarct dementia
  • the present disclosure provides methods of reducing plasma p-tau in a human subject having or suspected of having a disease associated with the accumulation and deposition of beta amyloid, such as Alzheimer's disease, Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and/or multi-infarct dementia.
  • beta amyloid such as Alzheimer's disease, Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and/or multi-infarct dementia.
  • provided methods comprise administering to a human subject an effective amount of an anti-beta-amyloid antibody.
  • the route of administration of an anti-beta-amyloid antibody of the present disclosure may be by any suitable route, including intravenous, subcutaneous.
  • an anti-beta-amyloid antibody, described herein is systemically administered to a human subject via infusion.
  • an anti-beta-amyloid antibody is administered to a human subject by subcutaneous injection.
  • an anti-beta-amyloid antibody is administered to the human subject by intravenous infusion.
  • the present disclosure provides methods that include administering an effective amount of an anti-beta-amyloid antibody to a human subject, where a level of plasma p-tau level has been or will be determined in the human subject.
  • an anti-beta-amyloid antibody is administered to a subject in one or more doses. In some embodiments, an anti-beta-amyloid antibody is administered to a subject as a multidose regimen.
  • compositions for use in treating a human subject with a disease associated with the accumulation and deposition of beta amyloid such as Alzheimer's disease, Down's syndrome, mild cognitive impairment, cerebral amyloid angiopathy, vascular dementia, and/or multi-infarct dementia.
  • a human subject has one or more characteristics.
  • a human subject is an ApoE carrier.
  • a human subject is aged ⁇ 65 years.
  • a human subject is aged 65 to 74 years.
  • a human subject is aged ⁇ 75 years.
  • the present disclosure provides compositions for use in treating a human subject with Alzheimer's disease, wherein a level of plasma p-tau has been determined prior to the treating.
  • a human subject has a plasma p-tau level prior to administration that is at or above a reference or threshold level.
  • a p-tau level in plasma comprises p-tau 181 and/or p-tau 217 .
  • the p-tau level is a plasma p-tau 181 level.
  • the present disclosure provides compositions for use in treating a human subject with Alzheimer's disease, wherein a level of plasma p-tau has been determined at a first time point that occurs prior to the treating and at a second time point.
  • a second time point for determining a p-tau level is after the human subject has received at least one dose of the anti-beta-amyloid antibody.
  • a second time point for determining the level of plasma p-tau is after at least 10 doses of anti-beta-amyloid antibody have been administered to the human subject.
  • a second time point for determining the level of plasma p-tau is after at least 14 doses of anti-beta-amyloid antibody have been administered to the human subject. In some embodiments, a second time point for determining the level of plasma p-tau is after at least 19 doses of anti-beta-amyloid antibody have been administered to the human subject.
  • the present disclosure provides compositions for treating a human subject whose change in plasma p-tau level between the first and second time point meets or exceeds a reference or threshold level.
  • a p-tau level in plasma comprises p-tau 181 and/or p-tau 217 .
  • the p-tau level is a plasma p-tau 181 level.
  • compositions comprise an anti-beta-amyloid antibody at a concentration of 50 mg/ml to 250 mg/ml; methionine at a concentration of 5 mM to 150 mM; Arg ⁇ HCl at a concentration of 50 mM to 200 mM; histidine at a concentration of 10 mM to 30 mM; PS80 at a concentration of 0.01% to 0.1%; and sucrose at a concentration of 0 to 3%.
  • a composition further comprises a thiol-containing antioxidant at a concentration of 0.02 mM to 4 mM.
  • a composition has a pH of 5.2 to 6.2.
  • a composition has a pH of 5.2 to 6.0. In some embodiments, a composition has a pH of 5.3 to 5.7. In some embodiments, a composition has a pH of 5.5.
  • the thiol-containing antioxidant is selected from the group consisting of GSH, GSSG, the combination of GSH and GSSG, cystine, cysteine, and the combination of cysteine and cystine. In some instances, the thiol-containing antioxidant is GSH. In some instances, the thiol-containing antioxidant is GSSG. In some instances, the thiol-containing antioxidant is the combination of GSH and GSSG.
  • a composition comprises an anti-beta-amyloid antibody at a concentration of 100 mg/ml; Arg ⁇ HCl at a concentration of 150 mM; methionine at a concentration of 10 mM; histidine at a concentration of 10 mM to 30 mM; PS80 at a concentration of 0.01% to 0.1%; and sucrose at a concentration of 0 to 3%.
  • a composition comprises an anti-beta-amyloid antibody at a concentration of 100 mg/ml; Arg ⁇ HCl at a concentration of 150 mM; methionine at a concentration of 10 mM; histidine at a concentration of 20 mM; and PS80 at a concentration of 0.05%.
  • a composition comprises an anti-beta-amyloid antibody at a concentration of 175 mg/ml; Arg ⁇ HCl at a concentration of 150 mM; methionine at a concentration of 10 mM; histidine at a concentration of 10 mM to 30 mM; PS80 at a concentration of 0.01% to 0.1%; and sucrose at a concentration of 0 to 3%.
  • a composition further comprises a thiol-containing antioxidant at a concentration of 0.02 mM to 4 mM.
  • the thiol-containing antioxidant is selected from the group consisting of GSH, GSSG, the combination of GSH and GSSG, cystine, cysteine, and the combination of cysteine and cystine. In some instances, the thiol-containing antioxidant is GSH. In some instances, the thiol-containing antioxidant is GSSG. In some instances, the thiol-containing antioxidant is the combination of GSH and GSSG.
  • a composition comprises an anti-beta-amyloid antibody at a concentration of 175 mg/ml; Arg ⁇ HCl at a concentration of 150 mM; methionine at a concentration of 10 mM; histidine at a concentration of 20 mM; and PS80 at a concentration of 0.05%.
  • a composition further comprises a thiol-containing antioxidant at a concentration of 0.02 mM to 4 mM.
  • the thiol-containing antioxidant is selected from the group consisting of GSH, GSSG, the combination of GSH and GSSG, cystine, cysteine, and the combination of cysteine and cystine.
  • the thiol-containing antioxidant is GSH.
  • the thiol-containing antioxidant is GSSG.
  • the thiol-containing antioxidant is the combination of GSH and GSSG.
  • kits comprising a composition comprising an anti-beta-amyloid antibody for administration to a human subject and instructions for use.
  • the instructions direct administration to a human subject that has one or more characteristics.
  • the instructions direct administration to a human subject that is an ApoE carrier.
  • the instructions direct administration to a human subject that has Down's syndrome.
  • the instructions direct administration to a human subject that is aged ⁇ 65 years.
  • the instructions direct administration to a human subject that is aged 65 to 74 years.
  • the instructions direct administration to a human subject that is aged ⁇ 75 years.
  • the instructions direct administration to a human subject that has a plasma p-tau level is above a reference or threshold level.
  • a p-tau level in plasma comprises p-tau 181 and/or p-tau 217 .
  • the p-tau level is a plasma p-tau 181 level.
  • kits for use in accordance with the present disclosure may include, instructions for processing samples, performing tests on samples, instructions for interpreting the results, etc.
  • the instructions to determine a p-tau level in plasma of a human subject at a first and second time point are prior to the human subject receiving a dose of the anti-beta-amyloid antibody.
  • a second time point for determining a p-tau level is after the human subject has received at least one dose of the anti-beta-amyloid antibody.
  • a second time point for determining the level of plasma p-tau is after at least 10 doses of anti-beta-amyloid antibody have been administered to the human subject.
  • a second time point for determining the level of plasma p-tau is after at least 14 doses of anti-beta-amyloid antibody have been administered to the human subject. In some embodiments, a second time point for determining the level of plasma p-tau is after at least 19 doses of anti-beta-amyloid antibody have been administered to the human subject.
  • the instructions direct continued administration to a human subject whose change in plasma p-tau level between the first and second time point meets or exceeds a reference or threshold level.
  • a p-tau level in plasma comprises p-tau 181 and/or p-tau 217 .
  • the p-tau level is a plasma p-tau 181 level.
  • Phase 3 studies recruited earlier-stage patients who were A ⁇ positive as assessed by A ⁇ PET scans (by visual read) and who fulfilled clinical criteria for either MCI due to Alzheimer's disease or mild Alzheimer's disease dementia (as defined by NIA-AA criteria). Enrollment was monitored such that approximately 80% of the Phase 3 study populations would include subjects with a baseline clinical stage of MCI due to Alzheimer's disease (per the investigator's clinical assessment). Subjects were also required to have a CDR global score of 0.5, an RBANS score of ⁇ 85 (based upon the Delayed Memory Index score), and an MMSE score between 24 and 30 (inclusive), and they must have had at least 6 years education or work experience. Subjects were to be 50 to 85 years of age at screening. Subjects with medical or neurological conditions other than Alzheimer's disease that may have contributed to the participant's cognitive impairment were excluded. Participants were to be in good health except for Alzheimer's disease.
  • Phase 3 protocols also required that subjects undergo ApoE genotyping, given the &4 allele is a major risk factor for Alzheimer's disease.
  • ApoE &4 carriers and noncarriers were enrolled in both Phase 3 studies; however, differential dosing based on carrier status was limited to only the aducanumab “low” dose. See, FIG. 1 .
  • the low dose group also had less decline on the CDR-SB than placebo; however, the differences were smaller than in the high dose group and did not attain statistical significance.
  • Negative percentage means less progression in the treated arm.
  • N numbers of all randomized and dosed subjects that were included in the analysis.
  • Data source t-mmse-mmrm-pc-new/Output 12, t-adas-mmrm-pc-new/Output 13, t-adl-mmrm-pc-new/Output 14, t-mmse-mmrm-cplt-new/Output 15, t-adas-mmrm-cplt-new/Output 16, t-adl-mmrm-cplt-new/Output 17
  • Brain A ⁇ was measured on PET and quantified as Standard Uptake Value Ratio (SUVR).
  • SUVR Standard Uptake Value Ratio
  • Serial assessment of brain A ⁇ plaque levels as measured by A ⁇ PET and quantified as SUVR was conducted in the subset of subjects participating in the longitudinal A ⁇ PET sub-study. PET scans in the longitudinal sub-study were performed using the 18 F-florbetapir A ⁇ PET tracer (except for a small number of subjects in whom another tracer was used). Results for the participants with 18 F-florbetapir PET scans are summarized here.
  • SUVR standard uptake value ratio
  • FIG. 2 depicts the time- and dose-dependent reductions in brain A ⁇ levels.
  • the adjusted mean change from baseline in A ⁇ PET composite SUVR was ⁇ 0.070 and ⁇ 0.076 in the low and high dose groups, respectively, compared with 0.007 in the placebo group. Due to the similarity of dosing during the titration phase, separation between the low and the high dose groups was not anticipated.
  • the adjusted mean change from baseline in A ⁇ PET composite SUVR was ⁇ 0.165 and ⁇ 0.272 in the low and high dose groups, respectively, compared with 0.019 in the placebo group.
  • results of the mITT and OTC analyses of the secondary endpoints show no statistically significant differences in decline on MMSE, ADAS-Cog13, or ADCS-ADL-MCI compared with placebo (Table 5). However, small numeric advantages for the low dose over placebo was observed on these endpoints. For ADAS-Cog13, or ADCS-ADL-MCI, results for the high dose group were similar to the low dose group.
  • Negative percentage means less progression in the treated arm.
  • N numbers of all randomized and dosed subjects that were included in the analysis.
  • Data source t-mmse-mmrm-pc-new/Output 12, t-adas-mmrm-pc-new/Output 13, t-adl-mmrm-pc-new/Output 14, t-mmse-mmm-cplt-new/Output 15, t-adas-mmrm-cplt-new/Output 16, t-adl-mmrm-cplt-new/Output 17
  • Brain A ⁇ was measured on PET and quantified as Standard Uptake Value Ratio (SUVR).
  • SUVR Standard Uptake Value Ratio
  • a longitudinal A ⁇ PET sub-study was conducted using the 18 F-florbetapir A ⁇ PET tracer.
  • FIG. 3 aducanumab resulted in time- and dose-dependent reductions in brain A ⁇ levels.
  • the adjusted mean change from baseline in A ⁇ PET composite SUVR was ⁇ 0.066 in both the aducanumab low and high dose groups, compared with ⁇ 0.002 in the placebo group.
  • the adjusted mean change from baseline in A ⁇ PET composite SUVR was ⁇ 0.168 and ⁇ 0.238 in the aducanumab low and high dose groups, respectively, compared with ⁇ 0.005 in the placebo group.
  • Example 4 Plasma Levels of p-Tau from Study 1 and Study 2
  • the present example describes an analysis of effects of treatment with an exemplary anti-A ⁇ antibody, aducanumab, on plasma p-tau levels, specifically, plasma p-tau 181 levels using data from the Phase 3 aducanumab trials described in Examples 1-3.
  • the adjusted mean change in in plasma p-tau 181 levels were assessed for patients treated with placebo, low dose anti-A ⁇ antibody and high dose anti-A ⁇ antibody, and results are shown in FIG. 4 and FIG. 5 for the populations of Study 1 and Study 2, respectively.
  • Mean baseline plasma p-tau 181 levels between treatment groups and in Studies 1 and 2 were 3.264 pg/mL and 3.185 pg/mL, respectively; and median baseline levels were 2.980 pg/mL in Study 1 and 3.080 pg/mL in Study 2.
  • a time-dependent increase in plasma p-tau 181 from baseline was seen in both Study 1 and Study 2 (8% and 9% increase from baseline, respectively).
  • the effect of aducanumab on plasma p-tau 181 levels also increased as the total cumulative dose increased.
  • the mean cumulative dose received up to week 78 were 127 in Study 1 and 122 in Study 2. Subgroup analysis of subsets of high dose subjects defined by the total cumulative dose received up to week 78 was performed. Relative reduction versus placebo between aducanumab treatment groups in mean change from baseline in plasma p-tau 181 was seen across all three cumulative dose groups ( ⁇ 100 mg/kg; 110-149 mg/kg, and ⁇ 150 mg/kg). Also, a greater treatment effect on plasma p-tau 181 levels with greater total cumulative dose (data not shown). For the highest total cumulative dose at week 78 ( ⁇ 150 mg/kg), a reduction from baseline in plasma p-tau 181 , levels was observed in both Study 1 and Study 2 (17% and 19% reduction, respectively).
  • This example describes a relationship between an anti-beta-amyloid antibody induced change in plasma p-tau levels, here p-tau 181 , and brain amyloid levels as expressed as amyloid PET standard uptake value ratios (SUVR).
  • p-tau 181 an anti-beta-amyloid antibody induced change in plasma p-tau levels
  • SUVR amyloid PET standard uptake value ratios
  • Subjects were assessed at week 78, and subjects were separated into the following categories: those receiving placebo (circles), those subjects receiving “low dose” anti-A ⁇ antibody treatment (squares), and those subjects receiving “high dose” anti-A ⁇ antibody treatment (triangles).
  • Example 6 Greater Reduction in Plasma p-Tau is Associated with Improved Clinical Measures
  • the present example describes a relationship between plasma p-tau levels and clinical outcomes. Specifically, a greater reduction in plasma p-tau, e.g., plasma p-tau 181 , was associated with less clinical decline by multiple measures of clinical efficacy. As shown in Table 8 below, correlations between plasma p-tau 181 and clinical efficacy were observed across four different clinical measures in patients from both Study 1 and Study 2, and in the expected directions.
  • the present example describes analysis of the effects of treatment with an anti-beta-amyloid antibody, aducanumab, on plasma p-tau levels in different subgroups assessed at week 78.
  • the present example provides subgroup analysis of plasma p-tau 181 levels in subjects of from Study 1 and Study 2, differentiated by age ( ⁇ 64, 65 to 74, or ⁇ 75 years), ApoE ⁇ 4 status (carrier or noncarrier), and baseline clinical stage (MCI due to AD or mild AD dementia).
  • Results are depicted in FIG. 9 (for low dose treated patients) and FIG. 10 (for high dose treated patients). Results were based on an MMRM (mixed model for repeated measures) model for each subgroup, with change from baseline as a dependent variable. Subgroup analysis was also performed based on sex (male/female) and baseline AD medication use (data not shown).
  • a reduction in plasma p-tau 181 was seen in both male and female subjects, and subjects stratified by AD symptomatic medication at baseline, in comparison with placebo. This reduction was seen across treatment groups (both low dose and high dose) in both studies at week 78, with no apparent trends between subjects stratified by sex or AD medication as baseline.
  • a reduction in plasma p-tau 181 is associated with improved clinical measures.
  • certain subgroups e.g., subjects ⁇ 75 years at baseline and/or subjects that are ApoE &4 noncarriers
  • anti-beta-amyloid antibody e.g., aducanumab
  • the plasma p-tau 181 subgroup analysis of the present example revealed a consistent reduction in plasma p-tau 181 levels in all participants treated with aducanumab, with an even greater decrease in those patients ⁇ 75 years old at baseline and in ApoE &4 noncarriers, which may be associated with improved benefits from treatment with aducanumab.
  • Example 8 Subgroup Analysis Based on Baseline Amyloid and Baseline p-Tau Levels
  • the present example describes further subgroup analysis of the effects of treatment with an anti-beta-amyloid antibody, aducanumab, on plasma p-tau levels. Specifically, the present example provides subgroup analysis of plasma p-tau 181 levels in subjects of from Study 1 and Study 2 at week 78, differentiated by baseline amyloid PET SUVR and baseline plasma p-tau 181 levels.
  • Results for subgroup analysis of baseline amyloid PET SUVR are depicted in FIG. 11 (for high dose treated patients) and FIG. 12 (for low dose treated patients).
  • Results for subgroup analysis of baseline plasma p-tau 181 levels are depicted in FIG. 13 (for high dose treated patients) and FIG. 14 (for low dose treated patients).
  • the present example describes analysis of the effect of treatment with an anti-beta-amyloid antibody, aducanumab, on plasma p-tau levels in a long-term extension study.
  • the long term extension study includes the placebo controlled trial period plus a long-term extension (LTE) period.
  • Subjects were randomized into “early start” and “late start” treatment groups.
  • Early start subjects are those who at the start of the placebo-control period were randomized to aducanumab and continued their originally assigned treatment in the LTE period, and include “early start low-dose” and “early start high-dose” subjects.
  • Late start subjects are those who at the start of the placebo-control period were randomized to placebo and then during the LTE period were randomized to receive dose-blinded aducanumab (low:high 1:1), and include “late start low-dose” and “late start high-dose” subjects.
  • results are depicted in FIG. 15 and FIG. 16 .
  • plasma p-tau 181 levels of late start subjects increased during the placebo-controlled period and started to reduce in the long-term extension period once subjects started to receive aducanumab treatment.
  • the late start high-dose group of subjects had a larger reduction in plasma p-tau 181 levels than the late start low-dose group, aligning with the larger exposure in the long-term extension up to week 128.
  • Comparison of the late start and early start groups within each study revealed statistically significant differences at both week 104 and week 128. For example, change from baseline in plasma p-tau 181 for the early start high-dose group compared to the late start high-dose group were and ⁇ 0.541 (p ⁇ 0.0001) and ⁇ 0.908 (p ⁇ 0.0001) at Week 104, and ⁇ 0.289 (p 0.1265) and ⁇ 0.640 (p ⁇ 0.0001) for Study 1 and Study 2, respectively. A similar trend was observed for subjects out to week 134 (data not shown).
  • the method further comprises a second administration of the anti-beta-amyloid antibody to the human subject.
  • the second administration of the anti-beta-amyloid antibody includes a dose of the anti-beta-amyloid antibody that is equal to or greater than the dose of the anti-beta-amyloid antibody administered to the human subject in the first administration.
  • the method further comprises a second administration of the anti-beta-amyloid antibody to the human subject.
  • anti-beta-amyloid antibody is selected from: aducanumab, lecanemab, gantenerumab, donanemab, LY3002813, bapineuzumab, crenezumab, MEDI-1814, and solanezumab.
  • anti-beta-amyloid antibody comprises:
  • anti-beta-amyloid antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO:2.
  • anti-beta-amyloid antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:10 and a light chain comprising the amino acid sequence of SEQ ID NO:11.
  • any one of embodiments 1-26, comprising administering the anti-beta-amyloid antibody as a multiple dose regimen comprising multiple doses of 1 mg antibody/kg of body weight of the human patient are administered to the human patient at intervals of 4 weeks, multiple doses of 3 mg antibody/kg of body weight of the human patient are administered to the human patient at intervals of 4 weeks, multiple doses of 6 mg antibody/kg of body weight of the human patient are administered to the human patient at intervals of 4 weeks, and multiple doses of 10 mg antibody/kg of body weight of the human patient are administered to the human patient at intervals of 4 weeks.
  • a method for selecting a patient for treatment with an anti-beta-amyloid antibody comprising determining a p-tau level in plasma of a human subject.
  • a method for determining a dose of an anti-beta-amyloid antibody to be administered to a human subject comprising determining a p-tau level in plasma of a human subject.
  • a method for selecting a patient receiving an anti-beta-amyloid antibody for cognitive support services comprising determining a p-tau level in plasma of a human subject.
  • a method comprising:
  • administering another dose of the anti-beta-amyloid antibody to the human subject comprises administering a dose of the anti-beta-amyloid antibody to the human subject that is equal to or greater than a prior dose of the anti-beta-amyloid antibody received by the human subject.
  • a method comprising
  • composition for use in a method accordingly to any one of embodiments 1 to 60 is not limited to any one of embodiments 1 to 60.
  • kits comprising a composition of embodiment 61 and instructions for use.
  • embodiment 63 or 64 wherein the treatment further comprises determining a p-tau level in plasma of the human subject at a first and second time point.
  • the treatment further comprises a second administration of the anti-beta-amyloid antibody to the human subject.
  • the treatment further comprises a second administration of the anti-beta-amyloid antibody to the human subject.
  • anti-beta-amyloid antibody is selected from: aducanumab, lecanemab, gantenerumab, donanemab, LY3002813, bapineuzumab, crenezumab, MEDI-1814, and solanezumab.
  • anti-beta-amyloid antibody comprises:
  • anti-beta-amyloid antibody comprises a VH comprising the amino acid sequence of SEQ ID NO: 1 and a VL comprising the amino acid sequence of SEQ ID NO:2.
  • anti-beta-amyloid antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 10 and a light chain comprising the amino acid sequence of SEQ ID NO:11.
  • any one of embodiments 63-85, wherein the treatment comprises administering a dose of the anti-beta-amyloid antibody in an amount of 3 mg antibody/kg of body weight of the human subject.
  • any one of embodiments 63-86, wherein the treatment comprises administering a dose of the anti-beta-amyloid antibody in an amount of 6 mg antibody/kg of body weight of the human subject.
  • any one of embodiments 63-87, wherein the treatment comprises administering a dose of the anti-beta-amyloid antibody in an amount of 10 mg antibody/kg of body weight of the human subject.
  • any one of embodiments 63-88 wherein the treatment comprises administering the anti-beta-amyloid antibody as a multiple dose regimen comprising multiple doses of 1 mg antibody/kg of body weight of the human patient are administered to the human patient at intervals of 4 weeks, multiple doses of 3 mg antibody/kg of body weight of the human patient are administered to the human patient at intervals of 4 weeks, multiple doses of 6 mg antibody/kg of body weight of the human patient are administered to the human patient at intervals of 4 weeks, and multiple doses of 10 mg antibody/kg of body weight of the human patient are administered to the human patient at intervals of 4 weeks.
  • any one of embodiments 63-89, wherein the treatment comprises administering a dose of the antibody at a cumulative dose of at least 150 mg antibody/kg of body weight of the human subject.
  • any one of embodiments 63-89, wherein the treatment comprises administering a dose of the antibody in an amount of 10 mg antibody/kg of body weight of the human subject every 4 weeks over at least 52 weeks.
  • any one of embodiments 63-89, wherein the treatment comprises administering a dose of the antibody in an amount of 6 mg antibody/kg of body weight of the human subject every 4 weeks over at least 112 weeks.
  • a method for selecting a patient for treatment with an anti-beta-amyloid antibody comprising determining a p-tau level in plasma, wherein the plasma is an in vitro sample that had been obtained from a human subject.
  • a method for determining a dose of an anti-beta-amyloid antibody to be administered to a human subject comprising determining a p-tau level in plasma, wherein the plasma is an in vitro sample that had been obtained from a human subject.
  • a method for selecting a patient receiving an anti-beta-amyloid antibody for cognitive support services comprising determining a p-tau level in plasma, wherein the plasma is an in vitro sample that had been obtained from a human subject.
  • a method comprising:
  • administering another dose of the anti-beta-amyloid antibody to the human subject comprises administering a dose of the anti-beta-amyloid antibody to the human subject that is equal to or greater than a prior dose of the anti-beta-amyloid antibody received by the human subject.
  • anti-beta-amyloid antibody is selected from: aducanumab, lecanemab, gantenerumab, donanemab, LY3002813, bapineuzumab, crenezumab, MEDI-1814, and solanezumab.
  • a medicament formulated as a dosing regimen comprising an anti-beta-amyloid antibody for use in a method for treating Alzheimer's disease (AD) in a human subject, wherein the dosing regimen comprises multiple doses of an anti-beta-amyloid antibody and wherein a p-tau level in plasma of the human subject has been determined at a first time point and a second time point.
  • AD Alzheimer's disease
  • the medicament of embodiment 124, wherein the anti-beta-amyloid antibody is selected from: aducanumab, lecanemab, gantenerumab, donanemab, LY3002813, bapineuzumab, crenezumab, MEDI-1814, and solanezumab.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Organic Chemistry (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cell Biology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Pathology (AREA)
  • General Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Food Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Peptides Or Proteins (AREA)
US18/707,366 2021-11-03 2022-11-02 Methods for treating alzheimer's disease Pending US20240425573A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US18/707,366 US20240425573A1 (en) 2021-11-03 2022-11-02 Methods for treating alzheimer's disease

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US202163275442P 2021-11-03 2021-11-03
US202163277127P 2021-11-08 2021-11-08
US202263309796P 2022-02-14 2022-02-14
US202263343029P 2022-05-17 2022-05-17
US18/707,366 US20240425573A1 (en) 2021-11-03 2022-11-02 Methods for treating alzheimer's disease
PCT/US2022/048684 WO2023081194A2 (en) 2021-11-03 2022-11-02 Methods for treating alzheimer's disease

Publications (1)

Publication Number Publication Date
US20240425573A1 true US20240425573A1 (en) 2024-12-26

Family

ID=86241855

Family Applications (1)

Application Number Title Priority Date Filing Date
US18/707,366 Pending US20240425573A1 (en) 2021-11-03 2022-11-02 Methods for treating alzheimer's disease

Country Status (5)

Country Link
US (1) US20240425573A1 (https=)
EP (1) EP4426349A4 (https=)
JP (1) JP2024540294A (https=)
TW (1) TW202325728A (https=)
WO (1) WO2023081194A2 (https=)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025240753A1 (en) * 2024-05-16 2025-11-20 Creative Bio-Peptides, Inc. Peptides and therapies for treating neurological disorders
CN118777453B (zh) * 2024-06-25 2025-04-08 上海交通大学医学院附属瑞金医院 一种基于液相色谱-串联质谱定量分析血液中仑卡奈单抗浓度的方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HRP20140049T1 (hr) * 2007-01-05 2014-02-28 University Of Zürich Anti beta-amiloid antitijela i njihova upotreba
EP2560681A4 (en) * 2010-04-22 2013-09-25 Janssen Alzheimer Immunotherap USE OF TAU FOR MONITORING IMMUNOTHERAPY
WO2014011972A1 (en) * 2012-07-13 2014-01-16 Bristol-Myers Squibb Company Tau immunoassay
NZ630542A (en) * 2012-08-16 2017-06-30 Ipierian Inc Methods of treating a tauopathy
WO2021016466A1 (en) * 2019-07-24 2021-01-28 Duke University Compositions and methods for the diagnosis and treatment of alzheimer's disease
KR20220084095A (ko) * 2019-10-22 2022-06-21 바이오젠 엠에이 인코포레이티드 알츠하이머병의 치료를 위한 항-베타-아밀로이드 항체

Also Published As

Publication number Publication date
EP4426349A2 (en) 2024-09-11
TW202325728A (zh) 2023-07-01
WO2023081194A3 (en) 2023-10-26
EP4426349A4 (en) 2025-10-29
JP2024540294A (ja) 2024-10-31
WO2023081194A2 (en) 2023-05-11

Similar Documents

Publication Publication Date Title
US20260091109A1 (en) Method for Treating Alzheimer's Disease
US20220281963A1 (en) Methods for treating alzheimer's disease
US20220372123A1 (en) Anti-beta-amyloid antibody for treating alzheimer's disease
US20240425573A1 (en) Methods for treating alzheimer's disease
US20250163135A1 (en) Biomarkers for alzheimer's disease treatment
CN120583962A (zh) 抗N3pGluβ淀粉样蛋白抗体、其剂量及其用途
US20250051427A1 (en) Methods of using an anti-amyloid beta protofibril antibody and anti-tau antibody
CN120826223A (zh) 鲨肌醇与免疫治疗剂组合用于治疗阿尔茨海默氏病
KR20240053620A (ko) 항-a베타 프로토피브릴 항체의 피하 제형 및 이를 사용하는 방법
US20240270830A1 (en) Methods for treating alzheimer's disease
CN118829445A (zh) 用于治疗阿尔茨海默病的方法
WO2025064824A1 (en) Methods for treating alzheimer's disease
WO2026057816A1 (en) Treatment of tauopathies with tau-binding antibodies
NZ788486A (en) Methods for treating Alzheimer's disease
EA052963B1 (ru) Способы применения антитела к протофибриллам бета-амилоида и антитела к тау-белку

Legal Events

Date Code Title Description
STPP Information on status: patent application and granting procedure in general

Free format text: APPLICATION UNDERGOING PREEXAM PROCESSING

AS Assignment

Owner name: BIOGEN MA INC., MASSACHUSETTS

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:NISENBAUM, LAURA;CHEN, TIANLE;RAJAGOVINDAN, RAJ;REEL/FRAME:067645/0688

Effective date: 20240529

STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION